180: Antifungal Therapy Flashcards
What are the two available groups of antifungals?
- polyene antibiotics
- azole derivates
What polyene antibiotic is used to treat systemic mycoses?
amphotericin B (AMB)
or lipid-complexed AMB
How is amphotericin produced?
by Steptomyces nodosus
How is the bioavailability of amphotericin B?
poor, requires parenteral administration
How does amphotericin distribute in the body?
- protein bound
- low volume of distribution
- poor CNS penetration
How does amphotericin kill fungal cells?
binds to ergosterol in fungal cell membranes –> increases membrane permeability and causes cell death
What toxicity does amphotericin cause and how?
nephrotoxicity
* binds to cholesterol in the proximal tubular cells –> causes renal vasoconstriction and renal tubular acidosis
What is the dosing protocol for amphotericin B?
- intermittent administration until a cumulative dosage has been achieved
- interruption of therapy in the event of azotemia
How do you administer amphotericin B?
diluted in 5% dextrose and over 1-5 hours IV to reduce nephrotoxicity
How do you monitor a patient for nephrotoxicity when undergoing amphotericin B treatment?
Before every dose BUN and urine sediment should be evaluated
* alter treatment regiments if tubular casts appear in urine sediment*
* if BUN exceeds 50 mg/dL discontinue treatment until azotemia resolves
*(earlier indicator than azotemia)
How do azole antifungals act against fungal cells?
inhibit the fungal P-450 enzyme necessary for development of ergosterol in fungal cell walls –> increased fungal cell permeability –> cell death
What are the classes of azoles and their antifungals?
triazoles:
* itraconazole
* fluconazole
* voriconazole
* pasoconazole
imidazoles:
* ketoconazole
* clotrimazole
* eniconazole
* miconazole
What are the main differences between triazoles and imidazoles?
triazoles:
* less effect on mammal sterol synthesis
* longer elimination times
imidazoles:
* more endocrine adverse effects
* greater effects on mammal sterol synthesis
Which one has best blood-brain penetration:
ketoconazole, fluconazole, or itraconazole?
Fluconazole
What drugs may lead to higher plasma drug concentrations of azoles?
drugs metabolized by hepatic P-450
What are adverse effects of ketoconazole therapy?
- GI upset
- induction of mammalial P-450 enzyem leading to elevation of ALT,AST, ALKP –> clinical hepatitis including fatalities has been reported
Which one is more hepatotoxic and why?
Ketoconazole
itraconazole more selectively inhibits fungal P-450 enzymes than mammalian ones –> limits its hepatotoxicity
What adverse effect is specific to the azole itraconazole?
cutaneous reactions consisting of localized ulcerative dermatitis andvasculitis
resolve following discontinuation of therapy
What arethe benefits of Fluconazole over Ketoconazole?
- more soluble –> greater BBB penetration, more consistent oral absorption on empty stomac*
- more potent
- less risks of metabolic adverse effects
*good for anorexic animals or CNS involvement
What is the treatment of choice for Blastomycosis?
Azoles
* similar response and occurence rates to amphotericin B but safer and more convenient administration
Fluconazole more cost effective than itraconazole
What is the treatment of choice for Histoplasmosis?
Azoles
* itraconazole most widely studied treatment for histoplasmosis in cats and dogs
* however, GI absorption not reliable in GI histoplasmosis or disseminated histoplasmosis
* consider fluconazole for better absorption and in animals with CNS involvement
GI histoplasmosis or severe disseminated disease
* parenteral amphotericin B combined with itraconazole or high dose itraconazole
How long should you treat an animal for Histoplasmosis?
- for at least 60 days OR
- until 1 month following resolution of clinical signs
How long should you treat Coccidioidomycosis
For at least 3-6 months beyond resoltution of clinical signs
What is the treatment of choice for coccidioidomycosis?
azoles
amphotericin B is indicated in animals with signficicant adverse ffects to azoles
What is the treatment of choice for Cryptococcisis?
Azoles
* preferentially fluconazole in CNS, eye, or uurinary tract involvement
How long are antifungals usually administered to treat cryptococcosis?
8-10 months
discontinue 1 month after resolution of clinical signs and decrease in antigen titer
